As illustrated in the following scheme, Mitsunobu reactions which employ triphenylphosphine and a dialkyl azodicarboxylate are capable of replacing hydroxyl groups with a wide variety of O, N, C, and halogen nucleophiles. Scheme I: ##STR1##
In contrast to many related condensation reactions, Mitsunobu reactions proceed under mild, essentially neutral conditions and exhibit stereospecificity, functional selectivity and regioselectivity. Because of these features the Mitsunobu reaction has been employed in synthesis of macrolide antibiotics, nucleosides, nucleoside phosphates, amino acids, amino sugars, steroids and other natural products. The method has been used to produce the anhydrothymidine precursor of the anti-AIDS drug azidothymidine (AZT), and in the direct preparation of the 3'-epimer of AZT from thymidine. More recently Mitsunobu conditions have been employed in the cyclization of .beta.-lactams and consequently have been used in synthesis of numerous monobactam antibiotics such as aztreonam, nocardicin A analogues, and carbapenem precursors. This invention has been devised to facilitate the large scale production of chemical and pharmaceutical products which are accessible through Mitsunobu-type reactions.
Given the wide variety of potential uses for the Mitsunobu reaction, particularly in the pharmaceutical industry, industrial scale applications of this technology would be of widespread benefit. To date it has been neither safe nor economically practical to use the Mitsunobu reaction in large-scale industrial applications. The prohibitive cost of the dialkyl azodicarboxylate reagent, and the required chromatographic purification of the product from triphenylphosphine oxide and dialkyl hydrazodicarboxylate (R00C--NHNH--C00R) side products, disfavor use of the Mitsunobu reaction. In addition, there is some danger of explosion on purification of the azodicarboxylate reagent by distillation. This invention overcomes these earlier limitations associated with the use of Mitsunobu reactions on an industrial scale, thereby expediting and facilitating this versatile condensation method for use in the synthesis of many pharmaceuticals and related compounds.